Circadian rhythm influences induction of trained immunity by BCG vaccination

Abstract

BACKGROUND. The antituberculosis vaccine bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes toward protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity. METHODS. Eighteen volunteers were vaccinated with BCG at 6 pm and compared with 36 age-and sex-matched volunteers vaccinated between 8 am and 9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as 2 weeks and 3 months after, BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8 am and 12 pm with BCG. RESULTS. Compared with evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning-compared with evening-isolated monocytes. CONCLUSIONS. BCG vaccination in the morning induces stronger trained immunity and adaptive responses compared with evening vaccination. Future studies should take vaccine administration time into account when studying specific and nonspecific effects of vaccines; early morning should be the preferred moment of BCG administration.

Seasonal and Daytime Variation in Multiple Immune Parameters in Humans: Evidence from 329,261 Participants of the UK Biobank Cohort

“…Previous studies have reported seasonal and circadian patterns in antibody titres in humans, 54 IgM 55 , often discovered serendipitously in the course of other investigations. 55 Leucocytes collected at different times of year showed decreased ex vivo response (thymidine incorporation, cytokine release) to activation in winter time in humans and rats [56][57][58]59 , and diurnal patterns in antibody titres 60 and in ex vivo response to stimulation of PBMCs 61,62 have been reported in humans. This study in UK Biobank is the first to investigate circadian and seasonal patterns in antibody titres to common infectious agents at a population level.…”

COVID-19 illness and autoimmune diseases: recent insights

“…A number of COVID-19 vaccine candidates have shown extremely promising results [ 26 ], which is expected to be used in the near future. Current treatment strategies of COVID-19 include symptomatic treatment and supportive care (oxygen, mechanical and circulatory support).…”

How could we forget immunometabolism in SARS-CoV2 infection or COVID-19?

“…BCG vaccination given in morning induces stronger trained immunity and adaptive immune phenotype after two weeks to three months compared to the evening vaccination in healthy adult volunteers [267]. Overall no trained immunity induces in people given evening vaccination.…”

“…The morning BCG vaccine receivers show an increase in circadian clock genes CLOCK and Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-like 1 (BMAL1) expression in their monocytes after one month along with an increase in histone 3 lysine 27 acetylation (H3K27ac, an epigenetic modification associated with gene activation) at the promoter of CLOCK and ARNTL genes [267]. The genes responsible for mTOR signaling (crucial for trained immunity induction) become more chromatin accessible in the morning vaccinated group, whereas evening vaccinated group show an increased chromatin accessibility to TNF and Nod-like receptor (NLR) signaling [267]. Morning receivers of BCG vaccine also show an increased transcription factor (TF) levels involved in mTOR signaling.…”